Fundamental to understanding the mechanisms of synaptic transmission in the central nervous system (CNS) is knowing the dimensions and connectivity of the pre- and postsynaptic elements and whether these factors change with synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are complementary, activity-dependent forms of synaptic plasticity that are considered to be important cellular models of learning and memory. Many of the physiological and molecular properties of LTP and LTD are being elucidated in hippocampal slices; however, almost nothing is known about the related structure of the synapses. The broad goal of this proposal is to test the hypothesis that synaptic structures play important roles in the regulation of synaptic plasticity during hippocampal development. The following key questions will be addressed: 1) is synapse structure affected by the making and maintaining of hippocampal slices in vitro? 2) which synaptic structures are likely to be needed for enduring LTP? 3) is synaptic structure altered by LTP or LTD in hippocampal slices? Methods: Hippocampal slices will be tested physiologically. Synaptic structure, number, composition, and connectivity will be quantified in the same slices, "blind" as to age and experimental condition, by the unbiased series sample method and representative three-dimensional reconstructions from serial electron microscopy. Health relatedness: In many human diseases involving mental retardation, synaptic structures, especially the postsynaptic dendritic spines, are grossly distorted. The distortions could disrupt the normal compartmentalization of molecules, such as calcium, in the heads of dendritic spines thereby preventing the development of enduring synaptic plasticity needed for LTP, LTD, and possibly other mechanisms of learning as well. Another detrimental effect of the loss of dendritic spine compartments is that high levels of calcium in dendrites and neurons could lead to excitotoxicity and cell death. The proposed research will delineate many aspects of synaptic structure which could be crucial for the development of normal synaptic transmission and plasticity in the central nervous system.